Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof
Inventors
Assignees
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Publication Number
US-11369600-B2
Publication Date
2022-06-28
Expiration Date
Abstract
Ophthalmic formulations containing nintedanib, or a pharmaceutically acceptable salt thereof are provided. The ophthalmic formulations can contain microparticles or nanoparticles of nintedanib. Also provided are methods of using the ophthalmic formulations for treating ocular surface diseases, such as dry eye disease.
Core Innovation
The invention relates to ophthalmic formulations comprising tyrosine kinase inhibitor particles, including nintedanib, or a pharmaceutically acceptable salt thereof, dispersed in an aqueous suspension. The formulations include at least one pharmaceutically acceptable excipient comprising about 0.01% to 0.3% (w/v) of tyloxapol. The disclosed framework supports administering a therapeutically effective amount of nintedanib-containing particles in an ocular delivery vehicle.
The disclosed formulations are characterized as aqueous suspensions and aqueous nanosuspensions, with nintedanib present as micronized particles or nanonized particles. Particle size characterization is described using D90 and D50 particle size metrics, including embodiments with reduced D90 and D50 particle size limits for nanosuspension particles. Formulation controls include selection of additional excipients such as viscosity regulators and specified pH ranges.
The patent also addresses formulation stability and performance in ocular-related contexts by describing nanosuspension manufacture and stability findings, including particle growth behavior over storage. Reported characterization and testing include suspension uniformity and particle sizing, and ocular tolerability and efficacy in a cornea suture-induced neovascularization context. Comparative evaluation is described between nintedanib ethanesulfonate and axitinib, with vehicle and Avastin comparisons.
Claims Coverage
The independent claims cover ophthalmic aqueous suspension and nanosuspension formulations containing nintedanib (or a pharmaceutically acceptable salt) with tyloxapol at about 0.01% to 0.3% (w/v), and methods of treating dry eye disease and a surface ocular disease by administering such formulations. Across the independent-claim set, the core inventive elements include the composition framework and method use of that composition for ocular indications. Dependent claims further refine particle form, particle size metrics, optional concentration ranges, viscosity regulator options, and suspension pH.
Ophthalmic aqueous suspension with tyloxapol
An ophthalmic aqueous suspension comprising a therapeutically effective amount of particles comprising nintedanib, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient comprising about 0.01% to 0.3% (w/v) of tyloxapol.
Treating dry eye disease with nintedanib tyloxapol suspension
A method of treating dry eye disease in a subject in need thereof by administering an ophthalmic formulation in the form of an aqueous suspension comprising a therapeutically effective amount of particles comprising nintedanib, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient comprising about 0.01% to 0.3% (w/v) of tyloxapol.
Treating a surface ocular disease with nintedanib tyloxapol suspension
A method of treating a surface ocular disease in a subject in need thereof by administering an ophthalmic formulation in the form of an aqueous suspension comprising a therapeutically effective amount of particles comprising nintedanib, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient comprising about 0.01% to 0.3% (w/v) of tyloxapol.
The claim set centers on using tyloxapol-formulated ophthalmic aqueous suspensions containing nintedanib (or a pharmaceutically acceptable salt) for ocular treatment. The independent claims require tyloxapol at about 0.01% to 0.3% (w/v) together with therapeutically effective nintedanib-containing particles, while dependent claims add nanosuspension format, particle size thresholds, defined viscosity regulator options, and suspension pH.
Stated Advantages
Improved ocular tolerability is reported in a rabbit ocular tolerability context.
Efficacy in corneal neovascularization is reported for nintedanib ethanesulfonate compared with vehicle and with Avastin.
Tyloxapol is reported to reduce particle growth and maintain nanosuspension particle size over storage.
Documented Applications
Treating dry eye disease by administering an ophthalmic formulation in the form of an aqueous suspension comprising nintedanib particles (or a pharmaceutically acceptable salt) and tyloxapol.
Treating a surface ocular disease by administering an ophthalmic formulation in the form of an aqueous suspension comprising nintedanib particles (or a pharmaceutically acceptable salt) and tyloxapol.
Ocular surface disease contexts including dry eye disease and corneal neovascularization in a rabbit model are described, including cornea suture-induced neovascularization with comparative evaluation versus vehicle and Avastin.
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